Detrimental effects of an inhaled phosphodiesterase-4 inhibitor on lung inflammation in ventilated preterm lambs exposed to chorioamnionitis are dose dependent

Background: Treatment of bronchopulmonary dysplasia in preterm infants is challenging due to its multifactorial origin. In rodent models of neonatal lung injury, selective inhibition of phosphodiesterase 4 (PDE4) has been shown to exert anti-inflammatory properties in the lung. We hypothesized that GSK256066, a highly selective, inhalable PDE4 inhibitor, would have beneficial effects on lung injury and inflammation in a triple hit lamb model of Ureaplasma parvum (UP)-induced chorioamnionitis, prematurity, and mechanical ventilation. Methods: Twenty-one preterm lambs were surgically delivered preterm at 129 days after 7 days intrauterine exposure to UP. Sixteen animals were subsequently ventilated for 24 hours and received endotracheal surfactant and intravenous caffeine citrate. Ten animals were randomized to receive twice a high (10 μg/kg) or low dose (1 μg/kg) of nebulized PDE4 inhibitor. Results: Nebulization of high, but not low, doses of PDE4 inhibitor led to a significant decrease in pulmonary PDE activity, and was associated with lung injury and vasculitis, influx of neutrophils, and increased proinflammatory cytokine messenger RNA levels. Conclusion: Contrary to our hypothesis, we found in our model a dose-dependent proinflammatory effect of an inhaled highly selective PDE4 inhibitor in the lung. Our findings indicate the narrow therapeutic range of inhaled PDE4 inhibitors in the preterm population

Novel SCARB2 mutation in action myoclonus-renal failure syndrome and evaluation of SCARB2 mutations in isolated AMRF features

Background: Action myoclonus-renal failure syndrome is a hereditary form of progressive myoclonus epilepsy associated with renal failure. It is considered to be an autosomal-recessive disease related to loss-of-function mutations in SCARB2. We studied a German AMRF family, additionally showing signs of demyelinating polyneuropathy and dilated cardiomyopathy. To test the hypothesis whether isolated appearance of individual AMRF syndrome features could be related to heterozygote SCARB2 mutations, we screened for SCARB2 mutations in unrelated patients showing isolated AMRF features. Methods: In the AMRF family all exons of SCARB2 were analyzed by Sanger sequencing. The mutation screening of unrelated patients with isolated AMRF features affected by either epilepsy (n = 103, progressive myoclonus epilepsy or generalized epilepsy), demyelinating polyneuropathy (n = 103), renal failure (n = 192) or dilated cardiomyopathy (n = 85) was performed as high resolution melting curve analysis of the SCARB2 exons. Results: A novel homozygous 1 bp deletion (c.111delC) in SCARB2 was found by sequencing three affected homozygous siblings of the affected family. A heterozygous sister showed generalized seizures and reduction of nerve conduction velocity in her legs. No mutations were found in the epilepsy, renal failure or dilated cardiomyopathy samples. In the polyneuropathy sample two individuals with demyelinating disease were found to be carriers of a SCARB2 frameshift mutation (c.666delCCTTA). Conclusions: Our findings indicate that demyelinating polyneuropathy and dilated cardiomyopathy are part of the action myoclonus-renal failure syndrome. Moreover, they raise the possibility that in rare cases heterozygous SCARB2 mutations may be associated with PNP features

The Ambivalent State: Determining Guilt in the Post-World War II Soviet Union

In the aftermath of the Second World War, the search for alleged traitors took place in each country that had been under foreign occupation. The most active country in this regard was the Soviet Union. This article analyzes how the Soviet authorities dealt with people who had lived in German-occupied territory during the war. It discusses divergent understandings of guilt, and examines means of punishment, retribution and justice. I argue that inconsistencies in Moscow’s politics of retribution, apart from reflecting tensions between ideology and pragmatism, resulted from contradictions within ideology, namely the belief that the war had uncovered mass enemies in hiding, and the belief that it had been won with the mass support of the Soviet population. The state that emerged from the war, then, was both powerful and insecure, able to quickly reassert its authority in formerly German-occupied areas, but also deeply ambivalent about its politics of retribution

Climatic and edaphic controls over tropical forest diversity and vegetation carbon storage

Tropical rainforests harbor exceptionally high biodiversity and store large amounts of carbon in vegetation biomass. However, regional variation in plant species richness and vegetation carbon stock can be substantial, and may be related to the heterogeneity of topoedaphic properties. Therefore, aboveground vegetation carbon storage typically differs between geographic forest regions in association with the locally dominant plant functional group. A better understanding of the underlying factors controlling tropical forest diversity and vegetation carbon storage could be critical for predicting tropical carbon sink strength in response to projected climate change. Based on regionally replicated 1-ha forest inventory plots established in a region of high geomorphological heterogeneity we investigated how climatic and edaphic factors affect tropical forest diversity and vegetation carbon storage. Plant species richness (of all living stems >10 cm in diameter) ranged from 69 to 127 ha-1 and vegetation carbon storage ranged from 114 to 200 t ha-1. While plant species richness was controlled by climate and soil water availability, vegetation carbon storage was strongly related to wood density and soil phosphorus availability. Results suggest that local heterogeneity in resource availability and plant functional composition should be considered to improve projections of tropical forest ecosystem functioning under future scenarios

Anti-inflammatory Effects of Heme Oxygenase-1 Depend on Adenosine A2A- and A2B-Receptor Signaling in Acute Pulmonary Inflammation

Acute pulmonary inflammation is still a frightening complication in intensive care units. In our previous study, we determined that heme oxygenase (HO)-1 had anti-inflammatory effects in pulmonary inflammation. Recent literature has emphasized a link between HO-1 and the nucleotide adenosine. Since adenosine A2A- and A2B-receptors play a pivotal role in pulmonary inflammation, we investigated their link to the enzyme HO-1. In a murine model of pulmonary inflammation, the activation of HO-1 by hemin significantly decreased polymorphonuclear leukocyte (PMN) migration into the lung. This anti-inflammatory reduction of PMN migration was abolished in A2A- and A2B-knockout mice. Administration of hemin significantly reduced chemokine levels in the BAL of wild-type animals but had no effects in A2A-/- and A2B-/- mice. Microvascular permeability was significantly attenuated in HO-1-stimulated wild-type mice, but not in A2A-/- and A2B-/- mice. The activity of HO-1 rose after LPS inhalation in wild-type animals and, surprisingly, also in A2A-/- and A2B-/- mice after the additional administration of hemin. Immunofluorescence images of animals revealed alveolar macrophages to be the major source of HO-1 activity in both knockout strains—in contrast to wild-type animals, where HO-1 was also significantly augmented in the lung tissue. In vitro studies on PMN migration further confirmed our in vivo findings. In conclusion, we linked the anti-inflammatory effects of HO-1 to functional A2A/A2B-receptor signaling under conditions of pulmonary inflammation. Our findings may explain why targeting HO-1 in acute pulmonary inflammation has failed to prove effective in some patients, since septic patients have altered adenosine receptor expression

How Adhesion Molecule Patterns Change While Neutrophils Traffic through the Lung during Inflammation

In acute pulmonary inflammation, polymorphonuclear cells (PMNs) pass a transendothelial barrier from the circulation into the lung interstitium followed by a transepithelial migration into the alveolar space. These migration steps are regulated differentially by a concept of adhesion molecules and remain—despite decades of research—incompletely understood. Current knowledge of changes in the expression pattern of adhesion molecules mainly derives from in vitro studies or from studies in extrapulmonary organ systems, where regulation of adhesion molecules differs significantly. In a murine model of lung inflammation, we determined the expression pattern of nine relevant neutrophilic adhesion molecules on their way through the different compartments of the lung. We used a flow cytometry-based technique that allowed describing spatial distribution of the adhesion molecules expressed on PMNs during their migration through the lung in detail. For example, the highest expression of CD29 was found in the intravascular compartment, highlighting its impact on the initial adhesion to the endothelium. CD47 showed its peak of expression on the later phase of transendothelial migration, whereas CD11b and CD54 expression peaked interstitial. A pivotal role for transepithelial migration was found for the adhesion molecule CD172a. Thereby, expression may correlate with functional impact for specific migration steps. In vitro studies further confirmed our in vivo findings. In conclusion, we are the first to determine the changes in expression patterns of relevant adhesion molecules on their migration through the different compartments of the lung. These findings may help to further understand the regulation of neutrophil trafficking in the lung

Descemet Membrane Endothelial Keratoplasty in Eyes with Glaucoma Implants

Purpose. This study aims to analyze the feasibility of Descemet membrane endothelial keratoplasty (DMEK) in the management of corneal endothelial decompensation in eyes with glaucoma implants. Case Report. A 62-year-old male with bullous keratopathy after trabeculectomy and Baerveldt shunt implantation for contusion glaucoma of the right eye (case 1) underwent surgical tube trimming with a DMEK procedure. A 54-year-old male with Descemet stripping automated endothelial keratoplasty (DSAEK) failure and dislocation in the presence of an Ahmed glaucoma valve and an artificial iris in the right eye (case 2) was treated by removal of the DSAEK graft and subsequent DMEK procedure. In both eyes, the DMEK graft could be successfully inserted, unfolded, positioned in front of the glaucoma tube, and attached to the host stroma by air injection into the anterior chamber. Postoperatively, both corneas cleared with complete graft attachment and stable glaucoma tube position. After 3 days, peripheral graft detachment occurred in case 1 and was managed successfully with one intracameral air reinjection. Case 2 revealed intraocular pressure (IOP) elevation up to 30 mm Hg in the immediate postoperative period, treated successfully by antiglaucoma medications. Within 1-year follow-up, visual acuity improved from hand movements to 20/63 and 20/32, respectively; endothelial cell density decreased by 36% and 42%, respectively; and the IOP ranged between 7 and 14 mm Hg in both cases without treatment. Conclusions. Descemet membrane endothelial keratoplasty seems to be feasible in the management of corneal endothelial decompensation in eyes with glaucoma implants. Graft attachment, IOP, and endothelial cell density should be followed up closely